Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia
Year: 2026
Type: article
Abstract: Mutations in NOTCH1 , which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/N WT ) or mutated (CLL/N M ), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/N M . These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/N WT ) or mutated (MEC-1/N M ) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/N M cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/N WT . Importantly, CLL/N M cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1 -mutated CLL.
Source: Leukemia
Authors: Amelia Fascì, Francesco Edoardo Vallone, Nahal Nabelsi, Elodie Viry, Ilenia Sana, Alessia Morabito, Silvia Seghezzi, Noemi Anna Pesce, Matteo Rovere, Nadia Bertola, Chloé Duculty, Silvia Ravera, Samir Mouhssine, Marta Muzio, Paolo Ghia, Candida Vitale, Marta Coscia, Etienne Moussay, Gianluca Gaidano, John Allan, Richard R. Furman, Jerome Paggetti, Tiziana Vaisitti, Silvia Deaglio
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
OpenAlex ID: W7140113320